The hedgehog (Hh) signaling pathway is a key developmental pathway which regulates patterning, growth and cell migration during embryonic development, but in adulthood is limited to tissue maintenance and repair. Under normal conditions, the endogenous ligands sonic hedgehog, Indian hedgehog and desert hedgehog bind to their receptor Patched (Ptch) which in turn relieves the inhibitory effect of Ptch on smoothened (Smo). Smo activation triggers a series of events ultimately lead to specific gene expression mediated by the Gli family transcription factors (Jiang and Hui, Dev. Cell Review (2008) 15:801-812). Aberrant Hh signaling has been linked to numerous human cancers. Mutational inactivation of the inhibitory pathway components leads to constitutive ligand-independent activation of the Hh signaling pathway, results in cancers such as basal cell carcinoma and medulloblastoma (Xie et al., Nature (1998) 391:90-92), glioblastoma (Bar et al. Stem Cells (2007) 25(10):2524-33; Filbin et al. Nature Medicine (2013) dio:10.1038/nm.3328). Ligand-dependent activation of Hh signaling is involved in prostate cancer (Sanchez et al. PNAS 101(2004) (34):12561-566), pancreatic cancer (Thayer et al. Nature (2003) 423:851-856), breast cancer (Kubo et al. Cancer Res. (2003) 64:6071-6074), non-small cell lung cancer (Yuan et al. Oncogene (2007) 26:1046-1055), small cell lung cancer (Watkins et al. Nature (2003) 422:313-317), and some blood cancers (Scales et al., Trends Pharmacol. Sci. (2009) 30:303-312). Therefore, inhibition of the aberrant Hh signaling represents a promising approach toward novel anticancer therapy (Peukert and Miller-Moslin, Chem Med Chem (2010) 5:500-512).
It has been found that hedgehog signaling regulates the expression of the ABC transporter proteins multi-drug resistance protein-1 (MDR1, ABCB1, P-glycoprotein) and (BCRP, ABCG2), and that targeted knockdown of MDR1 and BCRP expression by small interfering RNA partially reverses Hh-induced chemoresistance. This indicates the Hh pathway maybe a target to overcome MDR and increase chemotherapeutic response (Sims-Mourtada et al. Oncogene (2007) 26:5674-79). The blockade of sonic hedgehog signaling pathway was found to enhance the antiproliferative effect of EGFR inhibitors in pancreatic cancer cells (Hu et al. Acta Pharmacol. Sin. (2007) 28 1224-30) and prostate cancer cells (Mimeault et al. Int. J. Cancer (2006) 118:1022-31).
The hedgehog pathway has also been associated with tumor regrowth after chemoradiotherapy and as a potential target to improve radiation response (Sim-Mourtada et al. Clin. Cancer Res. (2006) 12:6565-6572).
It has also been reported that the inhibition of the hedgehog signaling pathway may be of use for the treatment of a range of diseases related to inflammation, epithelial cell hyperplasia, fibrosis of tissue or immune disorders (Lamb et al. EP1183040).

Cyclopamine, a naturally occurring alkaloid, was the first reported Hh signaling pathway inhibitor (Cooper et al., Science (1998) 280:1603-1607), and later identified as Smo antagonist (Chen et al., Genes. Dev. (2002) 16:2743-2748). A cyclopamine derivative IPI-926, which demonstrated better potency, stability and other pharmaceutical properties than that of cyclopamine, has entered clinical development (Trembley et al., J. Med. Chem. (2009) 52:4400-4418). One embryonic pathway inhibitor, GDC-0449 (Robarge et al., Bioorg. Med. Chem. Lett. (2009) 19: 5576-5581), was approved by FDA in January 2012 for the treatment of basal cell carcinoma which is not suitable for operation.
Despite advances with these compounds, there are numerous problems. For example, GDC-0449 possesses all sp2-hybridized carbons but one, thereby resulting in high melting point (251° C.) and poor solubility (9.5 μg/mL)—the enhanced solubility was obtained by adding an ortho-chloro group to the right side ring to introduce tilt and reduce planarity of the aryl amide (Robarge et al.). It also introduced mutations in SMO and resulted rapid tumor relapse in at least one patient (Yauch et al., Science (2009) 326:572-574). There remains a need to develop potent hedgehog pathway inhibitors.